Inhibition of integrin linked kinase (ILK) suppresses beta-catenin-Lef/Tcf-dependent transcription and expression of the E-cadherin repressor, snail, in APC-/- human colon carcinoma cells

Oncogene. 2001 Jan 4;20(1):133-40. doi: 10.1038/sj.onc.1204052.

Abstract

Loss of functional adenomatous polyposis coli (APC) protein results in the stabilization of cytosolic beta-catenin and activation of genes that are responsive to Lef/Tcf family transcription factors. We have recently shown that an independent cell adhesion and integrin linked kinase (ILK)-dependent pathway can also activate beta-catenin/LEF mediated gene transcription and downregulate E-cadherin expression. In addition, ILK activity and expression are elevated in adenomatous polyposis and colon carcinomas. To examine the role of this pathway in the background of APC mutations we inhibited ILK activity in APC-/- human colon carcinoma cell lines. In all cases, inhibition of ILK resulted in substantial inhibition of TCF mediated gene transcription and inhibition of transcription and expression of the TCF regulated gene, cyclin D1. Inhibition of ILK resulted in decreased nuclear beta-catenin expression, and in the inhibition of phosphorylation of GSK-3 and stimulation of its activity, leading to accelerated degradation of beta-catenin. In addition, inhibition of ILK suppressed cell growth in culture as well as growth of human colon carcinoma cells in SCID mice. Strikingly, inhibition of ILK also resulted in the transcriptional stimulation of E-cadherin expression and correlated with the inhibition of gene transcription of snail, a repressor of E-cadherin gene expression. Overexpression of ILK caused a stimulation of expression of snail, but snail expression was found not to be regulated by beta-catenin/Tcf. These data demonstrate that ILK can regulate beta-catenin/TCF and snail transcription factors by distinct pathways. We propose that inhibition of ILK may be a useful strategy in the control of progression of colon as well as other carcinomas. Oncogene (2001) 20, 133 - 140.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli / enzymology
  • Adenomatous Polyposis Coli / genetics
  • Adenomatous Polyposis Coli Protein
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cadherins / physiology*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism*
  • Cytoskeletal Proteins / antagonists & inhibitors*
  • Cytoskeletal Proteins / deficiency
  • Cytoskeletal Proteins / genetics*
  • Cytoskeletal Proteins / physiology
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology
  • Genes, APC
  • Humans
  • Integrins / physiology
  • Lymphoid Enhancer-Binding Factor 1
  • Neoplasm Proteins / deficiency
  • Neoplasm Proteins / genetics
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / genetics
  • Repressor Proteins / physiology
  • Snail Family Transcription Factors
  • Trans-Activators*
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / genetics
  • Transcription Factors / physiology
  • Transcription, Genetic*
  • Tumor Cells, Cultured
  • beta Catenin

Substances

  • Adenomatous Polyposis Coli Protein
  • CTNNB1 protein, human
  • Cadherins
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Integrins
  • Lymphoid Enhancer-Binding Factor 1
  • Neoplasm Proteins
  • Repressor Proteins
  • Snail Family Transcription Factors
  • Trans-Activators
  • Transcription Factors
  • beta Catenin
  • integrin-linked kinase
  • Protein-Serine-Threonine Kinases